N,N-diethyl-2-(α-naphthoxy)propionamide is known as napropamide, and its racemic mixture is generally marketed under trade name as “Devrinol”. It is used for pre-emergence control of annual grasses and broad-leaved weeds in many crops and plantations.
The second carbon atom at the propionamide group in napropamide has a hydrogen atom, a methyl group, a naphthoxy moiety and a carboxamide group thereby forming a chiral center. Hence the molecule [Fig I] can exist in two chiral stereoisomers: D or (R) and L or (S)-isomers.
Various processes reported in the literature for the synthesis of this compound generally result in producing different mixture of these isomers, usually racemic mixtures and they are difficult to separate.

Both D and L isomers and/or their racemic mixtures of the compound N,N-diethyl-2-(α-naphthoxy)propionamide have herbicidal activity. However, Chan et al., J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported that the (D)-isomer of napropamide shows 8 times more activity than the (L)-isomer and 1.7-2 times more than it's racemic mixture, for certain weeds. Thus, effective herbicidal compositions can be made using about half the quantity of the current racemic napropamide.
Various synthetic strategies have been reported for the preparation of optically active 2-arylpropionamide and their different homologues as for e.g., (a) optically active base for resolving recemates. (b) a resolution of diasteromeric derivatives as salts of esters, anhydrides (c) biochemical methods (asymmetric hydrolysis of esters or oxidation of aromatic hydrocarbons (T. Sugai and K. Mori, Agric. Bio. Chem., 48, 2501 (1984)) or (d) stereo-specific reactions where starting material is having chiral center.
Various processes have been reported for the preparation of D-(−)-N,N-diethyl-2-(α-naphthoxy)propionamide. Published literatures relevant to this subject are given below, in chronological order. However, the exact chemical as well as chiral purity of the D-(−) product obtained by some of these processes has not been reported.
U.S. Pat. No. 3,480,671 (1969) (Tilles et al), describes the preparation of racemic N,N-diethyl-2-(α-naphthoxy)propionamide from α-naphthol and N,N-diethyl-bromo propionamide in methanol as solvent and by using sodium methoxide.
U.S. Pat. No. 3,718,455 (1973) (Baker et al) discloses the process for the preparation of the D-isomer of the napropamide. According to this process, the resolution of dl-2-(α-naphthoxy)propionic acid results in d-acid of 90% purity and 1-acid of 85% purity. The process further discloses the conversion of the d-acid into acid chloride in DMF by using phosgene. The acid chloride is then converted into D-isomer of N,N-diethyl-2-(α-naphthoxy)propionamide through the amidation by using diethyl amine and triethyl amine as acid acceptor. The molar yield of D-isomer of N,N-diethyl-2-(α-naphthoxy)propionamide as disclosed in the patent is 61%.
Preparation by this process produced product in overall low yield. The chemical or chiral purity of the product was not addressed by this process. Further, this process involves resolution technique, which is highly expensive and time consuming. Hence, this process is not suitable for commercial manufacture of D-isomer of N,N-diethyl-2-(α-naphthoxy)propionamide.
James H. H Chan et al, J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported the procedure for the D-isomer of the napropamide. The process involves the use of L (+) form of lactic acid as starting material and then conversion into ester and after subsequent reactions into D-isomer of napropamide. This process involves multi steps and overall yield is low. The process is also dependant on the availability of L (+) form of Lactic acid, which is not easily available. Therefore, this process is not suitable for large-scale preparation.
U.S. Pat. No. 3,998,880 (1976) (Simone et al) described the following process of preparing racemic N,N-diethyl-2-(α-naphthoxy)propionamide. The process comprises reacting 2-chloropropionic acid with diethyl amine in the presence of phosphoryl chloride giving an intermediate 2-chloropropionyl diethyl amide, which is then reacted with α-naphthol and sodium hydroxide to give N,N-diethyl-2-(α-naphthoxy)propionamide. However, this process teaches the preparation of racemic N,N-diethyl-2-(α-naphthoxy)propionamide.
U.S. Pat. No. 4,548,641 (1985) (Walker et al) described the two methods for the preparation of optically active isomer of N,N-dialkyl-2-(4-substituted-α-naphthoxy)propionamide. According to the first method, optically active lower alkyl ester of 2-halopropionic acid is reacted with 4-substituted α-naphthol, to produce optically active 4-substituted-α-naphthoxy propionic acid. This acid is then converted into acid chloride by using phosgene and subsequently reacted with dialkyl amine to obtain the desired optically active isomer. This method involving conversion of lower alkyl ester of 2-halopropionic acid to the optically active 4-substituted-α-naphthoxy propionic acid gives low yield and may give some by-product (e.g., furan type ring condensed with a naphthalene ring) which was very difficult to be separated from the desired product.
According to the second method, optically active amide is prepared by reacting an ester with an amine in the presence of a promoter which is halide of a group IIIA metal having molecular weight of 26 or greater, or of a group IVB metal. This dialkylated amide is treated with substituted naphthol to produce a product with desired isomer. The products obtained by this method are not sufficiently rich in optical purity.
Lin Jin et al, Pesticides, 39, 18-20, (2000) reported different resolution process of the preparation of the optically active isomer. These resolution techniques involved very complex, tedious procedures and expensive resolving agents. The resolution techniques also required a large amount of solvent leading to the high cost.
There is therefore a need to make commercially available a highly pure optically active D-(−)-N,N-diethyl-2-(α-naphthoxy)propionamide for better herbicidal activity and a process suitable for making a commercially feasible high purity D-isomer of D-(−)-N,N-diethyl-2-(α-naphthoxy)propionamide.